1. Field of the Invention
The present invention relates generally to ches:cal compositions and their use in the treatment of neuropsychiatric disorders. More particularly, the composiitions comprise an amino acid derivative, 3-N-phenylacetylamino-2,6-piperidinedione (heretofore referred to as PAPD) useful in the treatment of neuropsychiatric disorders associated with monoamine oxidase regulation.
2. Background of the Invention
A need for new psychotropic agents arises from the toxicity and the limited efficacy of currently available compounds. Each class of psychotropic agents is plagued by side effects and/or toxic effects which limit their clinical utility: neuroleptics cause extrapyramidal syndromes and tardive dyskinesia; antidepressants cause atropinism and excess sedation; anxiolytics produce tolerance and sedation; and monoamine oxidase inhibitors alternatively cause hypotension or hypertensive crises. The limited effectiveness of existant psychotropics in treating selected patients with common neuropsychiatric disorders combined with these unwanted toxic effects produces a need for further psychotropic drug development.
A stereochemical model (U.S. Pat. No. 4,461,619, 1984) has already been developed to determine a priori both the biological activity and probable toxicity of a wide range of endogenous compounds and therapeutic agents. This list includes but is not limited to the following: sex hormones, thyroid hormones, glucocorticoids, mineralocorticoids, vitamins, antineoplastic agents, antibiotics, neurotransmitters and psychotropics. Other investigators have also been involved in finding novel psychotropic agents with two basic approaches: first, to improve existing compounds which presumably affect a neurotransmitter such as dopamine, serotonin, norepinephrine, GABA and/or acetylcholine; and second to develop new compounds which affect the above and peptide neurotransmitters such as endorphine, enkephalins, cholecystokinin, vasopressin, substance P and others.
3. Development of the Invention
Interest in developing effective and non-toxic agents, combined with a focus on peptides as possible new psychotropic agents, resulted in the discovery that an existing dipeptide agent PAPD fit in the stereochemical model in a way similar to existing psychotropics. Previous work with PAPD as an antineoplastic agent had demonstrated a lack of toxic effects. Moreover, clinical investigators noted both an elevation of mood and diminished need for analgesia in some cancer patients who were treated with PAPD. These clinical observations, combined with a fit of PAPD into a neurotransmitter/psychotropic model suggested that PAPD might be a dipeptide with psychotropic activity. The present applicants then postulated that PAPD might be an antipsychotic, antidepressant, anxiolytic and/or analgesic agent based on knowledge that substances with these various effects can elevate mood and/or reduce the need for analgesia.
Thereafter, an analysis of a PAPD was undertaken in vitro and in vivo beginning with antipsychotic (neuroleptic) and antidepressant activity. It was determined that PAPD lacked substantial neuroleptic activity based on both its inability to displace H.sup.3 -spiroperidol from rat caudate nucleus and inability to reverse apomorphine and amphetamine induced locomotor changes in rats. Investigation of PAPD's possible monoamine oxidase (MAO) inhibition by standard platelet analysis demonstrated a significant degree of MAO inhibition. The two distinct forms of the enzyme have been designated as type A (serotonin metabolizing and clorgyline sensitive) and type B (phenyethylamine metabolizing and clorgyline insensitive). Based on the stereochemical model, it was predicted that PAPD's effect on MAO type B would be greater than its effect on MAO type A. In vitro data has substantiated this prediction.
A large number of compounds are inhibitors of MAO, and the elevation of mood by some of these agents is believed to be related to the accumulation of one or more of these biogenic amines in the synaptic cleft. The clinical utility of these compounds is related to the treatment of depression, panic disorders and Parkinson's disease. However, this utility is hindered because of serious untoward effects, particularly the hypertensive crisis that may result following the ingestion of tyramine containing foods by patients taking certain MAO inhibitors. Because of the existence of two catalytic varieties of MAO which can be specifically inhibited by certain drugs, it is conceivable that the unwanted side effects may be eliminated by the use of specific and selective inhibitors.
In summary, the search for a new, effective, non-toxic psychotropic compound began with the investigation of an existing dipeptide analog, PAPD. PAPD fit into a stereochemical model like other known psychotropic agents. In vitro and in vivo analyses have shown PAPD to be an MAO inhibitor with inhibition of MAO type B greater than that for MAO type A.
Because the main clinical toxicity (hypertensive crisis from ingestion of tyramine) may relate to MAO type A inhibition, PAPD shows promise as a potentially clinically effective, non-toxic, relatively selective MAO type B inhibitor. At present there is one agent commercially available in the United States which is a relatively selective MAO type B inhibitor but it is used as an antihypertensive. A selective MAO type B inhibitor is of great clinical utility because of the potential for lack of a need for dietary restriction of tyramine containing food. This dietary restriction lisits the clinical utility of existing MAO inhibitors because of the patient's and physician's reluctance to risk toxicity by accidental ingestion of common foods as well as serious drug-drug interactions with conventional MAO inhibitors.